Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 9, Pages 5230-5248Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab282
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Funding
- Telethon Foundation [GGP19007, 20013]
- Fondation NRJ pour les Neurosciences -Institute de France Grant
- Associazione Luigi Comini Onlus
- Medical Research Council (MRC) [MC UU 00015/5, MC UU 00015/4, MC UU 00015/7]
- Marie Sklodowska-Curie ITNREMIX [721757]
- Swedish Research Council [2018-02439]
- Swedish Cancer Foundation [2019-816]
- European Research Council [2016-683191]
- Knut and Alice Wallenberg Foundation [KAW 2017.0080]
- MRC Graduate Student Fellowship
- EMBO Installation Grant [IG4149, TUBITAK 119C022]
- Bogazici University [SUP-15501]
- Telethon Foundation
- ERC
- Swedish Research Council [2018-02439] Funding Source: Swedish Research Council
- MRC [MC_UU_00015/4, MC_UU_00015/7, MC_UU_00015/5] Funding Source: UKRI
- Marie Curie Actions (MSCA) [721757] Funding Source: Marie Curie Actions (MSCA)
- Formas [2018-02439] Funding Source: Formas
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Mutations in the POLG gene cause a range of disorders characterized by mtDNA instability. Researchers generated a mouse model with the A449T mutation, which impairs POL gamma activity and leads to reduced levels of POL gamma A, suggesting a potential target for future therapies.
Mutations in POLG, encoding POL gamma A, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the Polg(A449T/A449T) mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POL gamma, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POL gamma B, the accessory subunit of the POL gamma holoenzyme. This allows the free POL gamma A to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POL gamma A in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POL gamma B acts to stabilize POL gamma A and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POL gamma subunits. We suggest that targeting POL gamma A turnover can be exploited as a target for the development of future therapies. [GRAPHICS] .
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